Use of alkanoyl L-carnitines for the therapeutical treatment of chronic inflammatory bowel disease

ABSTRACT

The use of lower alkanoyl L-carnitines is disclosed for preparing pharmaceutical compositions (particularly foams and enemas) for treating chronic inflammatory bowel diseases, in particular ulcerative colitis.

This is a division of application Ser. No. 08/868,627, filed Jun. 4,1997, now U.S. Pat. No. 6,013,670, the entire content of which is herebyincorporated by reference in this application.

The present invention relates to a new therapeutic use of the loweralkanoyl L-carnitines and their pharmacologically acceptable salts toproduce pharmaceutical compositions for the treatment of chronicinflammatory bowel diseases, and, in particular, ulcerative colitis.

The present invention also relates to pharmaceutical compositionssuitable for rectal administration, particularly in the form of foams orenemas, containing the above-mentioned alkanoyl L-carnitines.

Ulcerative colitis is an inflammatory, ulcerative disease of the colonof unknown aetiology, very often characterised by haematic diarrhoea.

It usually originates in the recto-sigmoid area, from which it mayspread proximally with possible involvement of the entire colon.Alternatively, it may attack a substantial portion of the large bowelright from the outset.

The complications of ulcerative colitis are particularly severe: it hasbeen documented, in fact, that there is an enormous increase in the riskof colon cancer in patients suffering from ulcerative colitis. Theincidence of colon cancer increases with both involvement of the entirecolon and with a duration of disease exceeding 10 years.

In both the mild-to-moderate forms and the moderately or distinctlysevere forms of the disease, corticosteroids constitute the drugs ofchoice, namely hydrocortisone, betamethasone and prednisone.

In the mild-to-moderate forms, physiological solution containinghydrocortisone is administered via an enema which is retained in thebowel as long as possible.

In the moderately severe forms, systemic corticosteroid therapy isnecessary, consisting generally in 10-15 mg of prednisone t.i.d. orq.i.d. per os, which is capable of inducing drastic remission.

In the more severe forms requiring admission to hospital, thecorticosteroid therapy is administered parenterally.

Both the systemic and topical administration of these drugs gives riseto serious side effects, mainly related to interference with thehypothalamopituitary-adrenal axis.

The side effects due to topical treatment of ulcerative colitis withthese traditional corticosteroids are, for instance, transient orprolonged depression of adrenocortical function, weight gain, acne andmoon face.

Though it is well know, particularly in the moderately severe forms ofthe disease, that the daily corticosteroid dose can be gradually reducedto 10-20 mg per week after 1-2 weeks of treatment, even such lowcorticosteroid doses continue to induce harmful side effects, theelimination or at least the drastic reduction of which constitutes atherapeutic goal of primary importance.

The object of the present invention is to provide pharmaceuticalcompositions for the treatment of chronic inflammatory bowel diseases,particularly ulcerative colitis, which, while affording equivalenttherapeutic benefit, make it possible to use a lower daily dose ofcorticosteroid drug, with a consequent distinct reduction in the sideeffects induced by such drugs.

A further object of the present invention is to provide a composition ofthe above-mentioned type which enables complete remission of symptoms tobe achieved and which lends itself to rectal administration, in the formof a foam or enema, thus making it possible to avoid corticosteroidadministration via the parenteral route even in the most severe cases.

These objects are achieved according to the present invention by meansof the use of lower alkanoyl L-carnitines in which the alkanoyl group,straight or branched, has 2-6 carbon atoms and of theirpharmacologically acceptable salts to produce the aforementionedcompositions. The preferred alkanoyl L-carnitines are acetyl, propionyl,butyryl, isobutyryl, valeryl and isovaleryl L-carnitine. PropionylL-carnitine, butyryl L-carnitine and their pharmacologically acceptablesalts are particularly preferred.

What is meant by a pharmacologically acceptable salt of an alkanoylL-carnitine is any salt of the latter with an acid which does not giverise to unwanted toxic or side effects. These acids are well known topharmacologists and pharmacy experts.

Non-limiting examples of such salts are, for instance, chloride,bromide, orotate, acid aspartate, acid citrate, acid phosphate, fumarateand acid fumarate, lactate, maleate and acid maleate, acid oxalate, acidsulphate, glucose phosphate, tartrate and acid tartrate.

Though, according to the present invention, the alkanoyl L-carnitine andthe reduced dose of corticosteroid can be administered orally, thepreferred alkanoyl L-carnitine administration route is rectal. Inparticular, those forms of rectal administration, such as foams andenemas, are preferred, which allow prolonged contact between thealkanoyl L-carnitine and the intestinal tract affected by theinflammatory ulcerative disease.

The preparation of these forms and enemas and the choice of appropriatevehicles and excipients are well known to pharmacy experts.

These compositions capable of being administered by the rectal route maycontain additional active ingredients such as antidiarrhoea agents,antibiotics, anaesthetics, stool softeners and lubricants.

For example, an enema composition comprises from approximately 3 toapproximately 15 grams, preferably 6-12 grams, of alkanoyl L-carnitineand possible 400-600 mg of hydrocortisone or 20-50 mg of prednisone perliter of physiological solution.

Though the daily dose will depend, according to the judgment of theprimary care physician, on the subject's weight, age and generalcondition, it is generally advisable to administer 1-4 g/day--preferably2-3 g/day--of alkanoyl L-carnitine or a stoichiometrically equivalentamount of one of its pharmacologically acceptable salts. In thepreferred rectal administration form, an enema of 500-mL physiologicalsolution containing 5-10 g of alkanoyl L-carnitine--e.g. 6 g ofpropionyl L-carnitine--is administered twice daily.

Larger doses can safely be administered in view of the substantialnon-toxicity of the alkanoyl L-carnitines.

Details are given here below of a clinical study demonstrating theactivity of the compounds according to the invention.

Three male patients suffering from ulcerative rectocolitis diagnosed byendoscopy and histological examination of biopsy samples, with a BMI(Body Mass Index) of 25 kg/m² and a DCAI (Crohn's Disease ActivityIndex) of approximately 180 (Gastroenterology 70: 439-444, 1976; Vol.70) no. 3), on treatment with steroids (prednisone 0.20 mg/kg/day) weretreated twice daily for 2 months with an enema containing 6 g ofpropionyl L-carnitine dissolved in 500 mL of physiological solution.

After only one week's treatment an improvement in the clinical picturewas already noticeable with a reduction in the number of daily bowelmovements and an improvement in the consistency of the faeces, as wellas reduced losses of blood and mucus.

Later in the course of therapy, the subjective symptoms and theobjective clinical findings continued to improve with reduction of theCDAI to approximately 120 by the end of the second month.

Thanks to this improvement the patients were able to reduce theircortisone therapy to approximately 0.8 mg/kg/day.

The endoscopic investigation showed a distinct improvement of theulcerative lesions with areas of re-epithelialisation and non-friablemucosa on contact with the instrument.

The histological examination revealed a distinct reduction of theinflammation.

No side effects were observed, and patient compliance was optimal.

The results obtained show that by the end of the course of treatment theuse of propionyl L-carnitine had significantly reduced (by about 40%)the amount of steroid drug administered to the patients, thus leading toa substantial reduction in its side effects.

What is claimed is:
 1. A rectally administrable pharmaceutical composition for the treatment of a chronic inflammatory bowel disease consisting of 5 to 10 grams of an alkanoyl L-carnitine in 500 ml of physiological solution wherein said alkanoyl group is straight or branched and contains 2-6 carbon atoms, and the pharmacologically acceptable salts thereof, said pharmaceutical composition further comprising a pharmacologically acceptable excipient.
 2. The composition of claim 1 wherein said pharmacologically acceptable salt of alkanoyl L-carnitine is selected from the group consisting of chloride, bromide, orotate, acid aspartate acid citrate, acid phosphate, fumarate, acid fumarate, lactate, maleate, acid maleate, acid oxalate, acid sulphate, glucose phosphate, tartrate and acid tartrate.
 3. The composition of claim 1, wherein said composition is an enema or a foam.
 4. The composition of claim 1, further comprising a corticosteroid selected from the group consisting of hydrocortisone, betamethasone and prednisone, said composition further comprising a compound selected from the group consisting of an antidiarrheal agent, antibiotic, anesthetic, stool softener and lubricant.
 5. The composition of claim 4, containing 400 to 600 milligrams of hydrocortisone.
 6. The composition of claim 4, containing 20 to 50 milligrams of prednisone. 